1. Field of the Invention
The present invention relates to a 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative and a use thereof. More particularly, the present invention relates to a 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative and a pharmaceutically available salt thereof as a new compound exhibiting an inhibitory activity against various types of inflammation mediated by HMGB1 protein, and a pharmaceutical composition for preventing or treating a vascular inflammatory disease and infectious disease, which contains the derivative as an active ingredient.
2. Discussion of Related Art
Sepsis refers to systemic infection occurring when germs penetrate into a blood, and a fatal diseases since over 225,000 of people die of sepsis yearly only in the United State. Even though the cause of the disease is simple, the sepsis includes various ranges of inflammation mechanisms. Due to such complexity, Xirgis was approved by FDA in 2001 as the only drug for treating sepsis after more than 20 years of research. However, on October, 2011, because of the question on efficacy for the treatment of sepsis, Xigris disappeared from the market, and since then, there has not been an apparent drug.
First, in the ‘Proceedings of the National Academy of Sciences’, it is disclosed by Tracey et al. that a transcription factor, high-mobility group box 1 (HMGB1), induces a cytokine reaction of a host cell to bacteriotoxin, and thus research on HMGB1 as a target protein for treating sepsis started [Yang H, PNAS, 2010, 107, 11942-11947]. HMGB1 is known as a DNA binding protein to induce inflammation [Fink M P, Critical care, 2007, 11:229]. When cell death or necrosis occurs in immunocytes or non-immunocytes, HMGB1 is secreted [Anderson U, Annu. Rev. immunol., 2011, 29, 139-162]. Sepsis occurs by inducing attachment and transfer of immunocytes by increasing permeability of vein endothelial cells by HMGB1 secreted into a blood [Bae J S, Blood, 2011, 118, 3952-3959]. In macrophages and vein endothelial cells, HMGB1 binds to Toll like receptor-2, 4 (TLR-2, 4) or Receptor for the advanced glycation end products (RAGEs), thereby secreting TNF-alpha and IL-6, and NF-kB and ERK-1/2 are activated, leading to serious vascular inflammation [Hori O, J. Biol. Chem., 270, 25752-25761, Park J S, J. Biol. Chem., 2004, 279, 7370-7377].
It was found that at the 18 hours after cecal ligation and puncture (CLP) surgery using a CLP surgery mouse model having the highest relevance with sepsis, an HMGB1 level is largely increased, and thus a clinical symptom of the sepsis is developed [Wang H, J. Internal Med., 2004, 255, 320-331]. Afterward, when an antibody with respect to HMGB1 was administered at 24 hours, a survival rate was highly increased, and the approach was remarkable as the first cytokine treatment method effective even when after the antibody was administered at 8 hours after the CLP treatment [Wang H, Nat. Med. 2004, 10, 1216-1221]. Accordingly, an organ damage was prevented in an animal treated with an HMGB1 inhibitor, and a protective action against death was maintained [Wang H, Nat. Med. 2004, 10, 1216-1221]. A clinical research result in which HMGB1 is secreted from cells and exists in a plasma in a patient of trauma or sepsis was reported [Yang R, Molecular medicine, 2006, 12, 105-114]. It was confirmed that HMGB1 was increased in a plasma within the first week after diagnosis in most of sepsis or septic shock patients, and an organ damage caused by systemic inflammation was observed [Gibot S, Intensive Care Med, 2007, 33, 1347-1353, Sunden-Cullberg J, Crit. Care Med., 2005, 33, 564-573]. Based on such a research result, a vascular inflammatory disease and infectious disease including sepsis can be prevented or treated through regulation of an activity of HMGB1 protein.
Therefore, as the result of investigating a new compound which can be applied as a drug for treating vascular inflammation, the inventors designed and synthesized a 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative compound, and conducted a CLP-induced sepsis animal test using the prepared 2,5,6,7-tetrasubstituted thiazolo[4,5-b]pyridine derivative compound from understanding that an effect of inhibiting an activity of the HMGB1 protein has not been reported, thereby confirming that an excellent sepsis survival rate was obtained, and thus completed the present invention.